Efficacy and Safety of Iclepertin (BI 425809) in Patients with Schizophrenia: CONNEX, a Phase III Randomized Controlled Trial Program

These studies are funded by Boehringer Ingelheim. Rationale No effective pharmacological treatments are available for cognitive impairments in schizophrenia. Iclepertin (BI 425809), a glycine transporter-1 inhibitor, enhances N-methyl-D-aspartate receptor signaling by increasing synaptic levels of its co-agonist, glycine. In a Phase II proof-of-clinical-concept trial (NCT02832037) iclepertin was well tolerated and improved cognition in schizophrenia. The Phase III CONNEX program aims to confirm efficacy and safety of iclepertin in improving cognition/functioning across a large cohort of patients with schizophrenia. Methods The CONNEX program consists of 3 replicate randomized, double-blind, placebo-controlled parallel trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830). 586 patients/trial will be recruited across 41 countries, and randomized 1:1 to receive daily iclepertin 10 mg or placebo over 26 weeks. Primary efficacy endpoint: change from baseline (CfB) in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. Key secondary efficacy endpoints: CfB in total Schizophrenia Cognition Rating Scale score; CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety/tolerability data will be collected in an open-label safety extension study (CONNEX-X). Results The studies are currently recruiting (first participants enrolled Aug–Sept 2021), with completion expected in Q1 2025. Current study status, including screening failures and data collection experiences, are presented. Conclusions Most industry-sponsored studies testing compounds for cognitive deficits have failed to show proof-of-clinical concept. If successful, the CONNEX program would provide evidence for iclepertin as the first efficacious medication addressing cognitive impairments in schizophrenia.